A major impetus for the creation of the Cooperative Drug Development Group (CDDG) for the Treatment of Mental Illness program is the sobering fact that available pharmacotherapies for major depression are suboptimal in terms of speed of onset, efficacy, and tolerability. Current medications for severe, chronic mood disorders are not based on pathophysiological models of illness, but rather are variations of monoaminergic-based therapies. The present application proposes a collaboration between 3 entities with the focused goal of accelerating antidepressant drug discovery: (1) the Departments of Psychiatry and Neuroscience of the Mount Sinai School of Medicine, (2) the NIMH Intramural Mood and Anxiety Disorders Program, and (3) Organon Pharmaceuticals. The primary aim of this collaboration is to test a candidate drug, Org 24448, in a phase II proof-of-concept clinical trial in adult patients with moderately treatment-resistant unipolar major depressive disorder. Org 24448 represents a new treatment approach for depression, by potentiating the AMPA receptor subfamily of ionotropic glutamate receptors. This drug has been shown to have antidepressant features in preclinical models, as well as cognitive-enhancing qualities. AMPA receptor activation has also been shown to increase expression of growth factors such as brain derived neurotrophic factor (BDNF). Since there is growing evidence from neuroimaging and post-mortem studies that severe mood disorders are characterized by alterations in intracellular signaling cascades and impairments of cellular plasticity and resilience, promoting BDNF may provide a mechanism for its therapeutic efficacy. In this 2-site, 8-week, randomized, placebo-controlled clinical trial, we aim to compare Org 24448 to placebo in patients ages 21 to 55, with a diagnosis of recurrent or chronic MDD (without psychotic features). Approximately 90 patients with major depression will be recruited at each site over 3 years, in order to randomize 70 patients at each site (140 patients total). Two sites are necessary to achieve the sample size of eligible patients in a relatively short period of time. As major depressive disorder continues to pose a significant public health problem, with high rates of morbidity and mortality, robust and well-tolerated new treatments are necessary. If initial studies are promising, this compound will be investigated for longer-term use with the aims of improving the long-term prognosis of this devastating chronic illness. [unreadable] [unreadable]